Cationic polymethacrylate-copolymer acts as an agonist for β-amyloid and antagonist for amylin fibrillation

In human, amyloid-beta (Aβ) and islet amyloid polypeptide (hIAPP) aggregations are linked to Alzheimer’s disease and Type-2 Diabetes, respectively. There is significant interest in better understanding the aggregation process by using chemical tools. Here, we show the ability of a cationic polymethacrylate-copolymer (PMAQA) to quickly induce β-hairpin structure and promote fibrillation in Aβ40, and to constrain the conformational plasticity of hIAPP for several days and inhibit its aggregation at sub-micromolar concentrations. NMR experiments and atomistic molecular dynamics simulations reveal that PMAQA electrostatically interacts with Aβ40’s Glu22 and Asp23 followed by β-sheet induction while it binds strongly to the closest proximity of amyloid core domain (NFGAIL) of hIAPP and restrain its structural rearrangement. This study provides a valuable approach to develop polymer-based anti-amyloid inhibitors that may diminish the population of intermediates of Aβ40 or hIAPP.